Translational profiling of ET-insensitive cell populations in ER+ breast cancer reveals new therapeutic vulnerabilities

Endocrine therapy resistance in ER+ breast cancer remains a major therapeutic challenge in clinic. This study offers a robust workflow to identify ET-insensitive cell populations that persist under selective pressure of ET in clinical samples and experimental models. We demonstrated that these populations are transcriptionally diverse and not defined by ER status/activity or molecular subtype. Importantly, we developed a predictive therapeutic pipeline that enables identification of new drugs tailored to target ET-insensitive cell populations. These findings provide a clinically relevant strategy for overcoming ET resistance and support the integration of single-cell profiling and organoid modeling into precision oncology workflows.